Design, synthesis and antiviral evaluation of pyrazole and pyrazoline derivatives as novel inhibitors of flavivirus and pestivirus replication [Tesi di dottorato]

The Flaviviridae family represents a large group of viral pathogens which are divided, according to the current taxonomy, in four genera: Flavivirus (type spe¬cies, yellow fever virus (YFV)), Hepacivirus (type species, hepatitis C virus (HCV)), Pestivirus (type species, bovine virus diar¬rhea (BVDV)) and Pegivirus (type species, hepatitis G virus (HGV)). Despite the majority of these viruses are responsible for a wide range of severe diseases in humans and animals, specific antiviral therapies are currently available only for the treatment of HCV infections. The global, social and economic impact due to morbidity and even mortality associated with these infections, urgently demands effective therapeutic interventions. Following the researches undertaken in our laboratory on heterocyclic compounds with antiviral activity, the design, synthesis and antiviral evaluation of new classes of pyrazole and pyrazoline derivatives with potent and selective anti-Flavivirus or anti-BVDV activity is described in the present PhD thesis. By the antiviral screening of an in house library of compounds, N-(1,3-diphenyl-1H-pyrazol-4-yl)methyl]anilines were identified as a new class of potent and selective inhibitors of human respiratory syncytial virus (RSV) replication. Some derivatives were also endowed with a moderate activity against BVDV and against significant human pathogens belonging to the Flavivirus genus such as YFV, Dengue Virus (DENV) and West Nile Virus (WNV). The hit compounds exhibited activity in the micromolar range coupled with low cytotoxicity (CC50 > 100 µM) against the cell lines (MDBK and BHK-21) utilized for the in vitro assays. Therefore, the systematic modification of all the portions of the molecular scaffold was planned, in order to identify more active compounds and to maintain the low cytotoxicity of the hit compounds. In particular, potent and selective inhibitors of YFV replication were obtained by replacement of the 1-phenyl ring with the 1-phenylsulfonyl moiety. Pursuing our research on anti-Flaviridae compounds, we also devoted our attention to pyrazoline analogues of previously studied pyrazole derivatives. The antiviral screening of the novel series of 1,3,5-trisubstituted pyrazolines has led to the identification of new hit compounds with promising activity against YFV and BVDV. Time of addition experiments were performed to determine the possible step(s) in YFV replication cycle that is inhibited by two 1,3,5-triphenyl-pyrazolines selected for their high anti-YFV potency and selectivity. The results of these studies showed that both compounds exhibited maximal inhibition when added in the pretreatment of BHK-21 cells or during infection of cell cultures with YFV. A similar behavior was observed for the reference inhibitor 6-Azauridine, at higher concentrations. However, further investigations are necessary for the identification of the anti-YFV target of these pyrazoline derivatives.

diritti: info:eu-repo/semantics/openAccess
In relazione con info:eu-repo/semantics/altIdentifier/hdl/11573/931038
DESIDERI, Nicoletta
valutatori esterni: F. Corelli
A. Carta
MAI, Antonello

Tesi di dottorato. | Lingua: Inglese. | Paese: | BID: TD18047854